JP2018527103A - Intelligent continuous production method of drop pills by liquid cooling - Google Patents

Abstract

【Task】
A material supply step for weighing and conveying a plurality of materials, and 2) heating and mixing the materials conveyed in step 1) in stages to obtain a mixed material, The active ingredient RSD in the mixed material is 5% or less, the material melting and mixing step, 3) pressurizing and raising the temperature of the mixed material obtained in step 2), and homogenizing the active ingredient RSD being 5% or less A material is obtained, a homogenization step, 4) A drop pill is obtained after vibrationally dropping the homogenized material obtained in step 3), a drop pill is poured into a cooling liquid and cooled and then transported. Step 5) An intelligent continuous production method of liquid pills by liquid cooling including a deoiling step in which the cooling liquid on the surface of the liquid pills conveyed in Step 4) is removed by a tilted centrifugation method. The manufacturing method not only shortens the overall manufacturing process time, but also ensures that the drop pill product is more stable and uniform and adopts a high speed centrifuge method to rationalize the drop. Not only does the pills be deoiled to prevent the pills from becoming contaminated, but also improves the circulating utilization of the coolant.

Description

  The present invention relates to the field of pharmaceutical technology, and more particularly to a drug production facility for drop pills, and more particularly to an intelligent continuous production method for drop pills by liquid cooling.

  Drip pills are a traditional dosage form in Chinese herbal medicines, which are widely used due to many advantages such as short production cycle, fast drug effect, high drug stability and convenient for portable storage. Get support.

  Conventional methods for producing drop pills are basically a combination of natural dripping and liquid cooling, or a combination of a pressure drop method improved from the natural dripping method and liquid cooling. The disadvantages of this method are as follows. 1. Since the entire production process takes a long time and some volatile components contained in the raw material cause component volatilization, it is difficult to guarantee the uniformity and stability of the quality of the drop pill product. 2. There is no material supply system, and the uniformity of the active ingredient in the drop pill is reduced. 3. Furthermore, it is necessary to adopt a liquid cooling method to perform liquid-solid separation of the drop pills and the cooling liquid, but it is relatively difficult to operate the two liquids completely, Remains in the drop pills and causes contamination of the drop pills. 4. When the production volume needs to be adjusted, the conventional dripping equipment is generally only possible by changing the dripper and adjusting the pressure. The number of drippings is small, and in addition, the surface area is exchanged with a large amount of paraffin coolant. Therefore, the circulation efficiency is low, the energy consumption is large, the equipment volume is increased, the blind spot on the clean surface is likely to exist, and the risk of cross-contamination is great.

  In order to improve the conventional drop pill manufacturing method, the stability in the drop pill manufacturing process is ensured, the molding quality and production speed of the drop pill are improved effectively, Increasing, while simultaneously reducing energy consumption and coolant usage to prevent contamination of the drop pills is the development trend and research direction of improvements to current drop pill manufacturing methods.

  In response to the above-mentioned drawbacks and existing problems of the prior art, the present invention provides an intelligent continuous production method of liquid pills by liquid cooling, not only reducing the elapsed time of the overall production process, To ensure that the product is more stable and uniform, and by adopting a high speed centrifuge, the drop pills can be rationally deoiled to prevent the drop pills from being contaminated and cooled The purpose is to improve the liquid recycling rate.

In order to achieve the above-described object, specific technical aspects adopted by the present invention are as follows.
1) A material supply step for weighing and transporting a plurality of materials,
2) A material melting and mixing step in which a mixed material is obtained by stepwise heating and mixing the material conveyed in step 1), and an active ingredient RSD in the mixed material is 5% or less,
3) A homogenization step in which the mixed material obtained in step 2) is pressurized and heated to obtain a homogenized material having an active ingredient RSD of 5% or less,
4) A drop pill is obtained after vibrationally dropping the homogenized material obtained in step 3), dropping the drop pill into a cooling liquid and transporting it after cooling, a dropping step;
5) This is an intelligent continuous production method of liquid pills by liquid cooling including a deoiling step in which the cooling liquid on the surface of the liquid drops transported in step 4) is removed by a tilted centrifugal method.

  Furthermore, in the step 5), the centrifugal acceleration when removing by the inclined centrifugation method is 500 to 2000 G, the inclination advance angle is 40 ° to 90 °, and the removal time per drop pill is 30 s. Without exceeding, the direction of the central rotation axis to which the centrifugal acceleration is directed is the horizontal direction. That is, a horizontal centrifugal structure is adopted.

  Preferably, in step 5), the centrifugal acceleration upon removal by the tilted centrifuge method is 600 to 1800 G, the tilt advance angle is 50 ° to 80 °, and the removal time per drop pill is 20 s. Not exceed.

  Furthermore, in step 1), the weighing is a loss-in-weight weighing (that is, the acceleration is close to 0 when the material is weighed), where the weight ratio of the drug to the auxiliary material matrix is 1: 5 to 5: 1.

  Furthermore, in step 2), the elapsed time of stepwise heating and mixing of the material does not exceed 60 s, preferably does not exceed 30 s, and after heating the temperature of the solid state material in the material to 50 ± 10 ° C., The mixed material is obtained by mixing with the liquid state in the material, and the mixture is continuously heated to 55 ± 10 ° C., and the three steps of secondary mixing, deaeration, and conveyance are performed again in order, and the temperature of each step is 0 to 10 ° C. To rise. The temperature when the mixing process of the materials is completed is 80 ° C. or less, preferably 60 to 70 ° C.

  Furthermore, in step 3), in pressurizing and raising the temperature of the mixed material, the applied pressure is 50 to 200 MPa, preferably 70 to 160 MPa, and the temperature rises by 10 to 20 ° C. The temperature can reach 80-100 ° C., preferably 90-95 ° C. after completing the pressurization and temperature rise in the homogenization step. The outlet pressure of the homogenizer is 0.005 to 0.5 MPa, preferably 0.1 to 2 MPa.

  Furthermore, in step 4), the vibration dropping has a vibration frequency of 10 to 500 Hz, preferably 30 to 200 Hz, and the diameter of the dropped pill is adjusted by adjusting the outlet pressure of the homogenizer. It can be controlled to 1 to 10 mm, preferably 1 to 5 mm.

  Further, in step 4), the cooling liquid has a temperature gradient, the range is -15 to 60 ° C, preferably 0 to 50 ° C, and the drop pill removes the cooling liquid from the hot spot to the cold spot. pass. The initial temperature of the coolant at the bottom of the barrel is -15 to 25 ° C. As the liquid level of the coolant in the barrel rises, the temperature gradually rises from the bottom to the top, forming a temperature gradient with a gradient range of -15-60 ° C.

  Further, in step 4), the cooling liquid includes paraffin, methyl silicone oil, kerosene, and the like, preferably liquid paraffin.

  Further, the elapsed time of the vibration dropping and cooling in the step 4) does not exceed 60 s, and preferably does not exceed 30 s.

  Further, the plurality of materials includes a drug and an auxiliary material matrix, wherein the drug is an extract of one or a tandin complex selected from psycho, tandin, thixene, cuckoo, and sensinren extracts, preferably a tandin complex. It is a product extract. In addition, the composite formulation can be selected from active ingredients such as commercially available Chisen Iki drop, Cuckoo pepper drop pills, or Tandin complex drop pills, preferably an active ingredient of Tandin complex drop pills. The auxiliary material matrix is selected from polyethylene glycols, sorbitol, xylitol, lactitol, maltose, starch, methylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, gum arabic, alginic acid, dextrin, cyclodextrin, agar, lactose 1 More than a seed. Polyethylene glycol is preferred.

  As can be seen from the above description of the technical aspects, the steps of the method of the present invention are closely linked, are continuous operations, are flexible in batches, have uniform product quality between batches, and are stable. It has high productivity, low material residue, and the total production time of drop pills is less than 3 min. In the prior art, the volatilization of components due to some volatile components contained in the raw materials and the quality are low. Overcame the disadvantage of being unstable. The drop pill produced using the method of the present invention has excellent quality consistency, and the dose accuracy can reach 0.5 ‰ by adopting a loss-in-weight weighing.

  Furthermore, by controlling the outlet pressure of the homogenizing material, the size of the drop pill can be adjusted, and it is not necessary to change the dripper used in the dropping process, and it is easy to adjust the product specifications.

  In order to make the above features and advantages of the present invention clearer and easier to understand, the following detailed description will be given by way of examples.

Example 1 Preparation of Tanjin Complex Drop Pills Tanjin Sancytinjin extract 600 g, Borneol 5 g, and PEG-6000 auxiliary material 2000 g were each weighed precisely and then borneol and PEG-6000 were heated first. Mix the materials, heat the temperature to 55 ° C, and further mix with the tanjin sanchinin ginseng extract, continue to heat to 60 ° C and continue the steps of mixing, degassing, conveying etc. to the mixed material After that, the final temperature reached 65 ° C. and the mixing process time of the above materials did not exceed 60 s. The homogenous pressure is adjusted to 2000 MPa, the mixed material is further uniformly dispersed to reach nano-level dispersion, and the temperature of the material is further increased, and at the outlet of the homogenizer, the temperature of the mixed material is 80 ° C. The outlet pressure of the gasifier was 2 MPa. The mixed material is dropped by dripper vibration, the vibration frequency is adjusted to 50 Hz, the material is dropped into the barrel loaded with liquid paraffin, the distance from the dripper to the top of the liquid paraffin liquid surface is 300 mm, The height is 5 m, the diameter of the barrel is 100 mm, the initial temperature of the liquid paraffin inlet is −10 ° C., a temperature gradient is formed in the barrel from bottom to top, the gradient range is −10 to 50 After the material is dropped into liquid paraffin at a temperature of 0 ° C., the material dripped by sufficient cooling is cooled to a solid state pill by the effect of temperature, and the diameter of the dropped pill is 5 mm. Yes, the time for the dropping process described above did not exceed 60 s. After the drop pills were formed, the first oil was filtered through a sieve with liquid paraffin, followed by a deoiling step. The deoiler is a centrifuge placed horizontally, separating pills and paraffin oil under the condition of an acceleration of 2000G, and finally obtaining an uncoated tangin composite. The time did not exceed 30 s. Next, operations such as coating can be performed.

  By setting the production process using the manufacturing method described above, the productivity of all equipment reaches 100 kg / h, the material residue is less than 5 kg, and the time for the material to pass through the equipment is less than 3 min. The material supply accuracy can be controlled to 0.5%, and the dose accuracy can reach 0.5 ‰.

Example 2 Manufacture of Tandin Complex Drop Pills Take 600 g of Tandin Sancytinine extract, 5 g of borneol, and 3000 g of PEG-6000 auxiliary material and weigh each precisely, then heat borneol and PEG-6000 first. Mix the materials, heat the temperature to 50 ° C, and further mix with the tanjin sanchinin ginseng extract, continue to heat to 55 ° C and continue the steps of mixing, degassing, conveying etc. to the mixed material After that, the final temperature reached 70 ° C. and the mixing process time of the above materials did not exceed 30 s. The homogenous pressure is adjusted to 1500 MPa, the mixed material is further uniformly dispersed to reach nano-level dispersion, and the temperature of the material is further increased, and at the outlet of the homogenizer, the temperature of the mixed material is 90 ° C. The outlet pressure of the gasifier was 0.1 MPa. The mixed material is dropped by dripper vibration, the vibration frequency is adjusted to 500 Hz, the material is dropped into the barrel filled with liquid paraffin, the distance from the dripper to the top of the liquid paraffin liquid level is 1000 mm, The height is 10 m, the diameter of the barrel is 1000 mm, the initial temperature of the liquid paraffin inlet is 0 ° C., a temperature gradient is formed in the barrel from bottom to top, the gradient range is 0-60 ° C. Yes, after dropping the material into liquid paraffin, due to the effect of temperature, the material dropped by sufficient cooling is cooled to a solid pill, the diameter of the dropped pill is 2 mm, The time of the dropping process described above did not exceed 30 s. After the drop pills were formed, the first oil was filtered through a sieve with liquid paraffin, followed by a deoiling step. The deoiling device is a horizontally placed centrifuge, which separates the drop pills and paraffin oil under the condition of an acceleration of 1500G, and finally obtains an uncoated tangin composite. The process time did not exceed 20 s. Next, operations such as coating can be performed.

  By setting the production process using the manufacturing method described above, the productivity of all equipment reaches 120 kg / h, the material residue is less than 5.5 kg, and the time for the material to pass through the equipment is less than 2 min. The material supply accuracy can be controlled to 0.5%, and the dose accuracy can reach 0.6 ‰.

Example 3 Manufacture of Cuckoo Pepper Drop Pills 200 g of Cuckoo Pepper extract, 1 ml of patchouli oil, 2 ml of sesame leaf oil, and 40 g of polyethylene glycol were weighed accurately and then each was precisely weighed, and then the polyethylene glycol was first heated to mix the materials. The temperature is increased to 45 ° C., and further mixed with Cuckoo extract, patchouli oil, sesame leaf oil, and heated to 55 ° C., and the steps of mixing, degassing, conveying, etc. are continued for the mixed material. After doing so, the final temperature reached 70 ° C. and the mixing process time of the above materials did not exceed 60 s. The homogenous pressure is adjusted to 500 MPa, the mixed material is more uniformly dispersed to reach nano-level dispersion, and the temperature of the material is further increased, and at the outlet of the homogenizer, the temperature of the mixed material is 80 ° C. The outlet pressure of the gasifier was 0.05 MPa. The mixed material is dropped by dripper vibration, the vibration frequency is adjusted to 100 Hz, the material is dropped into a barrel loaded with liquid paraffin, the distance from the dripper to the top of the liquid paraffin liquid surface is 700 mm, The height is 8 m, the diameter of the barrel is 100 mm, the initial temperature of the liquid paraffin inlet is 5 ° C., a temperature gradient is formed in the barrel from bottom to top, the gradient range is 5-60 ° C. Yes, after dropping the material into liquid paraffin, due to the effect of temperature, the material dropped by sufficient cooling is cooled to a solid pill, the diameter of the dropped pill is 1 mm, The time for the dropping process described above did not exceed 50 s. After the drop pills were formed, the first oil was filtered through a sieve with liquid paraffin, followed by a deoiling step. The deoiling device is a centrifuge placed horizontally, separating pills and paraffin oil under the condition of acceleration of 500G, and finally obtaining uncoated cuckoo pepper, The time did not exceed 25s. Next, operations such as coating can be performed.

  By setting the production process using the manufacturing method described above, the productivity of all equipment reaches 95 kg / h, the material residue is less than 4.5 kg, and the time for the material to pass through the equipment is less than 3 min. The dose accuracy can reach 0.5 ‰ by controlling the material supply accuracy to 0.55%.

Example 4 Production of Senshinren Drop Pills 400 g of sensinlen, 800 g of PEG-6000 auxiliary material and 800 g of PEG-4000 auxiliary material were weighed and precisely weighed. After mixing the materials by heating, the temperature is heated to 55 ° C, and after the steps of mixing, degassing, conveying, etc. are continuously performed on the mixed materials, the final temperature reaches 70 ° C, and the above-mentioned materials are mixed The process time did not exceed 45 s. The homogenous pressure is adjusted to 1500 MPa, the mixed material is further uniformly dispersed to reach nano-level dispersion, and the temperature of the material is further increased, and at the outlet of the homogenizer, the temperature of the mixed material is 90 ° C. The outlet pressure of the gasifier was 5 MPa. The mixed material is dropped by dripper vibration, the vibration frequency is adjusted to 300 Hz, the material is dropped into the barrel filled with liquid paraffin, the distance from the dripper to the top of the liquid paraffin liquid surface is 300 mm, The height is 1 m, the diameter of the barrel is 500 mm, the initial temperature of the liquid paraffin inlet is 0 ° C., one temperature gradient is formed in the barrel from bottom to top, the gradient range is 0-60 ° C. Yes, after dropping the material into liquid paraffin, due to the effect of temperature, the material dripped by sufficient cooling is cooled to a solid pill, the diameter of the dropped pill is 10 mm, The time for the dropping process described above did not exceed 55 s. After the drop pills were formed, the first oil was filtered through a sieve with liquid paraffin, followed by a deoiling step. The deoiling device is a centrifuge placed horizontally, separating pills and paraffin oil under the condition of acceleration of 500G, and finally obtaining uncoated senshinren, the time for the above deoiling process Did not exceed 25 s. Next, operations such as coating can be performed.

  By setting the production process using the above manufacturing method, the productivity of all equipment reaches 110 kg / h, the material residue is less than 5.2 kg, and the time for the material to pass through the equipment is less than 2.5 min The material supply accuracy can be controlled to 0.6% and the dose accuracy can reach 0.55 ‰.

Comparative Example Conventional drop pill dripping: Tandin composite drop pills were produced using a drop pill machine production line disclosed in Chinese Patent ZL20081015133713.6.
Below, it demonstrates with a table | surface that this invention has a further advantage compared with the manufacturing method of the conventional drop pill.

  As can be seen from the above examples and comparative examples, the present invention not only shortens the elapsed time of the overall manufacturing process, but also ensures that the drop pill product is more stable and stable material. Guarantee having feeding accuracy and dosage accuracy. Moreover, by adopting a high-speed centrifugation method, the pills are rationally deoiled to prevent the pills from being contaminated, and the circulation utilization rate of the paraffin coolant is improved.

Claims (11)

1) a material supply step for weighing and transporting a plurality of materials,
2) A material melting and mixing step in which a mixed material is obtained by stepwise heating and mixing the material conveyed in step 1), and an active ingredient RSD in the mixed material is 5% or less;
3) A homogenization step in which the mixed material obtained in step 2) is pressurized and heated to obtain a homogenized material having an active ingredient RSD of 5% or less;
4) A dropping step in which a drop pill is obtained after the homogenized material obtained in step 3) is vibrated and dropped, and the drop pill is put into a cooling liquid and cooled and then transported;
5) An intelligent continuous production method of liquid drop pills by liquid cooling, including a deoiling step, wherein the cooling liquid on the surface of the liquid drop pills conveyed in step 4) is removed by an inclined centrifugal method.   In step 5), the centrifugal acceleration upon removal by the inclined centrifugation method is 500 to 2000 G, the inclination advance angle is 40 ° to 90 °, and the removal time per one drop pill does not exceed 30 s. The intelligent continuous manufacturing method of drop pills by liquid cooling according to claim 1, wherein the direction of the central rotation axis directed by the centrifugal acceleration is a horizontal direction.   In step 5), the centrifugal acceleration upon removal by the inclined centrifugation method is 600 to 1800 G, the inclination advance angle is 50 ° to 80 °, and the removal time per droplet does not exceed 20 s. The intelligent continuous manufacturing method of the drop pill by liquid cooling of Claim 2 characterized by the above-mentioned.   In step 1), the weighing is a loss-in-weight weighing, wherein the weight ratio of drug to auxiliary material matrix is 1: 5 to 5: 1. An intelligent continuous production method for drop pills.   In step 2), the elapsed time of the stepwise heating and mixing of the material does not exceed 60 s, the temperature of the solid state material in the material is heated to 50 ± 10 ° C. and then mixed with the liquid state in the material. A mixed material is obtained, which continues to be heated to 55 ± 10 ° C., and then repeats the three steps of secondary mixing, deaeration, and conveyance, and the temperature of each step increases by 0 to 10 ° C. The method for intelligent continuous production of drop pills by liquid cooling according to claim 1, wherein the temperature at the end of the process is 80 ° C. or less.   In step 3), after pressurizing and raising the temperature of the mixed material, the applied pressure is 50 to 200 MPa, the temperature rises by 10 to 20 ° C., and after the pressurization and temperature rise are completed in the homogenization step The method for intelligent continuous production of drop pills by liquid cooling according to claim 1, wherein the temperature reaches 80 to 100 ° C. and the outlet pressure of the homogenizer is 0.005 to 0.5 MPa.   In step 4), the vibration dropping has a vibration frequency of 10 to 500 Hz, and the diameter of the dropping pill is controlled to 1 to 10 mm by adjusting the outlet pressure of the homogenizer. The method for intelligent continuous production of drop pills by liquid cooling according to claim 6.   In step 4), the cooling liquid has a temperature gradient, the range is -15 to 60 ° C, and the drop pill passes through the cooling liquid from the high temperature part to the low temperature part, and the initial temperature of the cooling liquid at the bottom of the barrel The temperature of the drop pill by liquid cooling according to claim 1, characterized in that the temperature is -15 to 25 ° C, and the temperature gradually increases from bottom to top as the liquid level of the coolant in the barrel increases. Continuous manufacturing method.   The method of claim 1, wherein the cooling liquid is selected from paraffin, methyl silicone oil, or kerosene.   2. The method for intelligent continuous production of drop pills by liquid cooling according to claim 1, wherein the elapsed time of the vibration dropping and cooling in step 4) does not exceed 60 s. The plurality of materials includes a drug and an auxiliary material matrix, wherein the drug is an extract of one or a tangin complex selected from psycho, tandin, chicene, cuckoo, sensinren extracts, or a commercially available Selected from the active ingredients of Chisen Iki Droplet, Cuckoo Shower Droplet or Tanjin Complex Drop Pill,
The auxiliary material matrix is at least one selected from polyethylene glycols, sorbitol, xylitol, lactitol, maltose, starch, methylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, gum arabic, alginic acid, dextrin, cyclodextrin, agar, and lactose. The intelligent continuous manufacturing method of the drop pill by liquid cooling of Claim 1 characterized by these.